U.S. patent number 4,470,975 [Application Number 05/844,175] was granted by the patent office on 1984-09-11 for method and composition for the elimination of water from an animal body.
This patent grant is currently assigned to The Johns Hopkins University. Invention is credited to Hillard Berger, deceased, W. Gordon Walker.
United States Patent |
4,470,975 |
Berger, deceased , et
al. |
September 11, 1984 |
Method and composition for the elimination of water from an animal
body
Abstract
It has been found that certain insoluble hydrophilic
cross-linked polysaccharides are useful pharmaceutical agents in
diverting water elimination from the renal route to the
gastrointestinal route, and removing excess water from the body by
the gastrointestinal route. These properties are of specific
therapeutic value in the treatment of edema, water intoxication in
chronic renal failure, in reducing the frequency of hemodialysis,
and in the treatment of other forms of fluid retention such as
congestive heart failure, cirrhosis of the liver, and other
disorders associated with refractory swelling. Sephadex-brand
insoluble hydrophilic, cross-linked dextrans are preferred in the
practice of the invention.
Inventors: |
Berger, deceased; Hillard (late
of Baltimore, MD), Walker; W. Gordon (Baltimore, MD) |
Assignee: |
The Johns Hopkins University
(Baltimore, MD)
|
Family
ID: |
25292026 |
Appl.
No.: |
05/844,175 |
Filed: |
October 21, 1977 |
Current U.S.
Class: |
514/54; 514/57;
514/58; 514/59; 514/60; 514/869; 514/909; 536/103; 536/106;
536/112; 536/120; 536/18.5; 536/4.1; 536/56 |
Current CPC
Class: |
A61K
31/715 (20130101); Y10S 514/909 (20130101); Y10S
514/869 (20130101) |
Current International
Class: |
A61K
31/715 (20060101); C07H 031/72 () |
Field of
Search: |
;424/180
;536/112,106,56,103 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3624209 |
November 1971 |
Granatek et al. |
3627872 |
December 1971 |
Parkinson et al. |
3865807 |
February 1975 |
Narang et al. |
3934007 |
January 1976 |
Gussin et al. |
3962429 |
June 1976 |
Furuno et al. |
3983232 |
September 1976 |
Pekic et al. |
4002173 |
January 1977 |
Manning et al. |
4070460 |
January 1978 |
Gainer, Jr. |
4076930 |
February 1978 |
Ellingboe et al. |
|
Foreign Patent Documents
Primary Examiner: Brown; Johnnie R.
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
What is claimed is:
1. A method of treating edema in a host in need of such treatment
because of renal failure which comprises orally administering to
said host an effective amount of a water-insoluble hydrophilic,
cross-linked polysaccharide which is capable of absorbing water in
the lumen of the gastrointestinal tract and discharging the thus
bound water by passage from the alimentary canal in the normal
way.
2. A method according to claim 1 wherein said polysaccharide
consists essentially of a copolymerization product in a gel grain
form comprising a 3-dimensional macroscopic carbohydrate network,
obtained from a neutral carbohydrate selected from the group
consisting of dextran, sorbitol, starch, hydroxyethyl cellulose,
dextrin, and sucrose and a bifunctional organic substance selected
from the group consisting of epichlorohydrin, dichlorohydrin,
diepoxybutane, bisepoxypropyl ether, ethylene
glycol-bis-epoxypropyl ether, and 1,4-butan-diol-bis-epoxypropyl
ether, bonded together by ether bridges of the general type
--O--X--O-- wherein X representa an aliphatic radical containing
from 3 to 10 carbon atoms, the said copolymerization product being
water-insoluble but being capable of absorbing water with
swelling.
3. A method according to claim 1 wherein said polysaccharide is a
copolymerization product in gel grain form comprising a
3-dimensional macroscopic network of dextran substances, built-up
of chains of mainly alpha-1,6-glucosidically bonded glucose
residues, bonded together by ether bridges of the general type
--R--O--X--O--R--, wherein R represents the dextram substances and
X is an aliphatic radical containing from 3 to 10 carbon atoms, the
said copolymerization product being water-insoluble but being
capable of absorbing water with swelling.
4. A method for treating obesity which comprises administering
orally to a host in need of such treatment an effective amount of a
water-insoluble hydrophilic, cross-linked polysaccharide which is
capable of absorbing water with swelling in the lumen of the
gastrointestinal tract, said oral administration being effective to
eliminate the bound water via the gastro-intestinal route rather
than by the renal route.
5. A method for treating edema in a mammal in need of such
treatment which comprises administering orally to said mammal an
effective amount of a water-insoluble hydrophilic, cross-linked
polysaccharide which is capable of absorbing water with
swelling.
6. A method for treating obesity in a mammal in need of such
treatment which comprises administering orally to said mammal an
effective amount of a water-insoluble hydrophilic, cross-linked
polysaccharide which is capable of absorbing water with
swelling.
7. A method for reducing the frequency of dialysis to a mammal in
need of such treatment because of renal failure which comprises
orally administering to said mammal an effective amount of a
water-insoluble hydrophilic, cross-linked polysaccharide which is
capable of absorbing water with swelling, and eliminating the bound
water through the gastrointestinal route.
Description
BACKGROUND OF THE INVENTION
In certain diseases, particularly in kidney diseases, water
retention within an animal body presents serious difficulties. With
total failure of the renal system, water build-up in the body,
called edema, can lead to an accumulation in the blood of
constituents normally eliminated in the urine, producing a severe
toxic condition. This toxic condition can lead to death. The
conventional treatment for diseases of this nature is periodic
hemodialysis, where artificial kidney machines eliminate water and
toxins from the body.
The cost of dialysis is exceedingly high and the availability of
dialysis machines is not nearly as great as is convenient for both
the practitioner and the patient involved. Additionally, the
patient undergoing dialysis may suffer from significant
physiological and mental discomfort. For these reasons, it is
highly desirable to limit the frequency of dialysis to the minimum
number of treatments necessary to preserve health.
Dialysis accomplishes two major objectives, viz. it removes both
water and toxins from the body. The toxins are, primarily,
substances resulting from protein metabolism. By proper control of
the diet of the patient, particularly with regard to the amount of
protein in the patient's diet, the necessary frequency of dialysis
for removal of these toxins can be considerably reduced as compared
to the frequency required with an unrestricted diet. However,
unless the patient's consumption of water is severely limited,
frequent hemodialysis is still necessary for the removal of
water.
Restricting the patient's intake of water is generally very
difficult, since patterns of water consumption are often deeply
ingrained and changing these patterns may result in severe physical
and mental discomfort to the patient. Many patients are not able to
restrict their water intake to the minimum necessary for
substantial reduction in the frequency of required dialysis.
Accordingly, if a method can be provided for removal of water from
the body, then frequency of dialysis could be substantially
reduced. Dialysis would, however, still be required for the
periodic removal of protein derived toxins, but the frequency of
dialysis for this purpose would be far less than the frequency
normally required for the removal of both water and protein derived
toxins.
SUMMARY OF THE INVENTION
The present invention provides a method of treating edema and
thereby reducing the patient's need for dialysis treatment.
It is an object of this invention to treat edema with reduced
reliance on hemodialysis by decreasing the rate of renal
elimination of water.
It is a further object of this invention to treat edema with
reduced reliance on hemodialysis by increasing intestinal water
loss.
It is a further object of this invention to provide a new treatment
for diseases characterized by an abnormal excess accumulation of
fluid within the body, such as, congestive heart failure, cirrhosis
of the liver, nephrosis, and other renal diseases associated with
fluid retention.
It is a further object of this invention to provide a method of
removing water from the gastrointestinal tract, reduce
gastrointestinal transit time, and decrease caloric intake.
Surprisingly, it has been found that certain insoluble hydrophilic,
cross-linked polysaccharides are useful pharmaceutical agents in
diverting water elimination from the renal route to the
gastrointestinal route, and removing excess water from the body by
the gastrointestinal route; these properties being of specific
therapeutic value in the treatment of water intoxication in chronic
renal failure, in reducing the frequency of hemodialysis, and in
the treatment of other forms of fluid retention such as congestive
heart failure, cirrhosis of the liver, and other disorders
associated with refractory swelling. These pharmacological
properties also provide a means of reducing caloric intake, and
hence useful in the treatment of conditions such as obesity.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates the effect of treatment with insoluble,
hydrophilic, cross-linked dextrans according to the invention on
the weight of feces eliminated by treated rats. It will be noted
that the weight of feces of rats treated according to the present
invention increases significantly when compared to rats which did
not receive treatment.
FIG. 2 shows the effect of treatment with insoluble, hydrophilic,
cross-linked dextrans according to the invention on water content
as a percentage of the weight of feces of rats treated according to
the present invention. It will be noted that the water content of
feces of rats treated according to the present invention is
significantly higher than that of untreated rats.
FIG. 3 shows the effect of the use of insoluble, hydrophilic,
cross-linked dextrans according to the present invention on the
survival of rats with urethral ligation. It will be noted that rats
treated with insoluble, hydrophilic, cross-linked dextran according
to the present invention survived significantly longer than rats
which received no treatment.
FIGS. 4 and 5 illustrate the effect of administering insoluble,
hydrophilic, cross-linked dextran according to the invention on the
body weight of rats. It will be noted that shortly after the
beginning of treatment the body weight of treated rats began to
drop, becoming significantly lower than the body weight of
untreated rats.
FIGS. 6A and 6B illustrate the effect of treatment on the volume of
urine and water content of the feces of rats treated according to
the present invention. It will be noted that the volume of urine of
rats treated according to the present invention was substantially
lower than the volume of untreated rats, and that at the same time,
the water content of the feces of treated rats increased compared
to the water content of the feces of untreated rats.
FIGS. 7A and 7B illustrate the effect of treatment of various
concentrations of the preferred insoluble, hydrophilic,
cross-linked dextrans of the present invention on the volume of
urine of treated rats and the water content of the feces of treated
rats. After treatment was ended, the volume of urine and water
content of the feces of the rats were again measured and are also
illustrated.
DETAILED DESCRIPTION OF THE INVENTION
It has been found in accordance with the present invention that
certain insoluble hydrophilic, cross-linked polysaccharides have
the ability to bind and keep large quantities of water in the
gastrointestinal tract, and hence are useful in the treatment of
diseases characterized by an abnormal excess accumulation of fluid
within the body. The insoluble hydrophilic, cross-linked
polysaccharides of the present invention may be ingested by the
patient and during passage of these substances through the
digestive system, water passes from the body into the lumen of the
gastrointestinal system and is bound by these substances. The bound
water is then eliminated by passage from the alimentary canal in
the normal manner. As is known, water and urea readily penetrate
the lining of the lumen, and by the method of the present invention
are continuously bound within the lumen by the insoluble,
hydrophilic, cross-linked polysaccharides of the present invention.
By binding water and urea in the lumen of the gastrointestinal
system with the insoluble, hydrophilic, cross-linked
polysaccharides of the present invention, water passing from the
body into the gastrointestinal system cannot be taken back into the
body, with the result that there is a net decrease in the water
content of the body.
As can be appreciated from the foregoing, the insoluble
hydrophilic, cross-linked polysaccharides according to the
invention must be able to bind water in the gastrointestinal system
without being taken up into the body proper through the walls of
the intestinal lumen. Further, the insoluble hydrophilic,
cross-linked polysaccharides of the present invention must be
non-toxic, reasonably palatable, and non-digestible.
The insoluble hydrophilic, cross-linked polysaccharides which are
used in the present invention are hydroxyl-group containing
non-ionic substances, preferably modified dextrans. In addition to
dextrans, other hydroxyl-group containing insoluble hydrophilic
cross-linked polysaccharides which are useful in the present
invention include modified starch, dextrin, cellulose, and
polyglucose, and hydroxyl-group containing uncharged derivatives of
these substances or products obtained by a partial depolymerization
of the same, as well as fractions thereof.
The dextran or other polysaccharide macromolecules are modified by
cross-linking to give a three-dimensional network of polysaccharide
chains. Because of their high content of hydroxyl groups, these
cross-linked polysaccharides are strongly hydrophilic and swell
considerably in water. Various types of insoluble, hydrophilic,
cross-linked polysaccharides are available differing in their
swelling properties. The degree of swelling is an identifying
characteristic of these hydrophilic polysaccharides. The degree of
swelling reflects differences in the degree of cross-linkage of the
polysaccharides. As is well known in the art, the transport of most
organic molecules through the walls of the intestinal lumen
requires an active process, and it does not appear that such a
process exists for the insoluble hydrophilic, cross-linked
polysaccharides of the present invention.
The preparation of the insoluble, hydrophilic, cross-linked
polysaccharides used in the present invention is fully described in
a series of British and United States patents assigned to
Aktiebolaget Pharmacia, a Swedish company. These patents, each of
which is hereby incorporated by reference in the present
application, are:
______________________________________ British Patent U.S. Pat. No.
______________________________________ -- 3,002,823 854,715
3,042,667 936,039 3,275,576 and 3,277,025 974,054 3,208,994
1,013,585 -- ______________________________________
It is to be understood that the disclosures of the above-listed
British and United States patents are related, but are not
necessarily identical. For example, although Examples 1 to 14 of
U.S. Pat. No. 3,042,667 are virtually identical to Examples 4 to 18
of British Pat. No. 854,715, the disclosure and claims of the
British patent include both water soluble and water insoluble
hydrophilic cross-linked dextrans, whereas the United States patent
disclosure is limited to water-insoluble hydrophilic cross-linked
dextrans. The hydrophilic, cross-linked polysaccharides used in the
present invention are all of the water-insoluble type. The
disclosures of the five United States patents listed above, hereby
incorporated by reference in the present application, enable one of
ordinary skill in the art to prepare the insoluble, hydrophilic,
cross-linked polysaccharides useful in the present invention. The
four British patents listed above, as well as the disclosures of
U.S. Pat Nos. 3,300,474 and 3,542,759, hereby incorporated by
reference in the present application, are referred to for
additional disclosure of insoluble hydrophilic, cross-linked
polysaccharides useful in the present invention.
The preferred insoluble hydrophilic, cross-linked polysaccharides
used in the present invention are copolymerization products in the
form of gel grains comprising a three-dimensional macroscopic
network of dextran substances, built up of chains of mainly
alpha-1,6-glucosidically bonded glucose residues, bonded together
by ether bridges of the general type --R--O--X--O--R--, wherein R
represents the dextran substances and X is an aliphatic radical
containing from 3 to 10 carbon atoms, the copolymerization product
being water-insoluble but being capable of absorbing water with
swelling, the water regain of the product being within the range of
about 1 to 50 grams per gram of the dry gel product. The "water
regain" of the dry gel product is the amount of water in grams
which can be absorbed by one gram of the dry gel. The capacity of
swelling of the gelled product may be measured in terms of the
water regain. While water regain in the range of about 1 to about
50 grams of water per gram of dry gel product is preferred, dry gel
products exhibiting a water regain in the range of about 1 to about
85 grams of water, or even more, are useful in the practice of the
present invention. Indeed, it will be understood that the maximum
water regain of the product is limited by the ability of the
cross-linked polysaccharides used in the present invention to
resist degradation in the gastrointestinal system.
In general, the process for preparing the preferred insoluble
hydrophilic, cross-linked dextrans used in the present invention
can be characterized as a block polymerization process in which a
substituted dextran is reacted with a bifunctional organic
substance containing halogen and/or epoxy groups, capable of
reacting with the hydroxyl groups of the substituted dextran to
form ether-linkages. The reaction is conducted in the presence of
an alkaline substance which may function either as an acceptor for
the hydrohalide liberated as a result of the reaction (when the
reaction that forms the basis of the ether-formation is a
condensation in which a hydrohalide is split off), or the alkaline
substance may act as a catalyst when the reaction is a pure
reaction of addition. The block copolymers thus formed are
insoluble in water, but capable of swelling therein. Examples of
suitable alkaline substances are the alkali metal hydroxides,
preferably sodium hydroxide and the alkaline earth metal
hydroxides, and also tertiary amines and quaternary ammonium
hydroxides.
The block polymerization process takes place in the presence of
water and is catalyzed by the alkaline substances described above.
As previously stated, all essential details of the preparation of
the insoluble hydrophilic, cross-linked dextrans and other
polysaccharides used in the present invention are set forth in the
five United States patents incorporated by reference herein.
Additional details of the preparation of the hydrophilic
cross-linked polysaccharides useful in the present invention may be
found in four British patents incorporated by reference herein, and
in U.S. Pat. Nos. 3,300,474 and 3,542,759 incorporated by reference
herein.
The preferred insoluble, hydrophilic, cross-linked dextrans of the
present invention are sold by Pharmacia Fine Chemicals, Inc., 800
Centennial Avenue, Piscataway, N.J. 08854 under the trademark
Sephadex. Sephadex-brand insoluble, hydrophilic, cross-linked
dextrans are available from Pharmacia subsidiaries or
representatives in most countries of the world. A list of suppliers
may be obtained by writing directly to Pharmacia Fine Chemicals,
Inc., Uppsala, Sweden.
EXAMPLE 1
Five normal Sprague-Dawley rats were placed in metabolic cages and
urine output on standard rat chow and free access to water measured
for a period of five days. During this period, the mean urinary
excretion rate in milliliters per day for the entire group was
14.72.+-.0.95 (standard error of mean, hereinafter SEM). The
animals were subsequently given Sephadex (G-50) mixed with food in
equal proportions. They were maintained on this regimen for an
additional 7 days. During this latter treatment the mean daily
urinary excretion rate was 3.5.+-.0.48 (SEM) ml per day, a highly
significant difference.
EXAMPLE 2
Six Sprague-Dawley rats were divided into 2 groups of 3 each. One
group was given regular or standard rat chow and water ad lib and
the second group was given the rat chow ground and mixed with equal
parts of Sephadex (G 50) and permitted water ad lib. These studies
were carried out for a period of 9 days. During this 9 day period
the average daily water intake for the group that received no
Sphadex was 30.5 ml per day (.+-.1.6 ml SEM). During the same time,
they excreted an average daily urine output of 8.54.+-.0.66 ml per
day. In contrast, the group receiving Sephadex ingested more water,
an average daily intake of 46.72.+-.2.0 ml per day but put out no
measurable quantity of urine. For a subsequent 4 day period, the
Sephadex was discontinued and on day 3 and 4 of this last period
water intake and urine output for the 2 groups was
indistinguishable.
EXAMPLE 3
The quantity of water excreted by way of the feces was measured in
10 animals. Ten male Sprague-Dawley rats were given Sephadex G 100
mixed in 1 to 1 ratio with pulverized purina rat chow. In 6 of the
animals the weight of the feces excreted per day was determined. In
4 animals the water content of the feces was measured. The results
of the study are shown in FIGS. 1 and 2. Fecal excretion per animal
on the control day was 7 grams and the water content 65%. Thus, at
the beginning of the study the animals were excreting approximately
4.5 ml of water in the feces. This rose steadily during this study
so that by day 7 the animals were excreting 20 grams of feces per
day per animal and the water content had risen to 90%. Thus, the
fecal water loss after 7 days on the Sephadex regimen was 18 ml per
day and increased fecal water loss of more than four-fold. This
increased water loss in the feces was even greater than average
daily urinary excretion volumes in control animals cited in
experiment 2 above. Thus the combination of examples of 1, 2 and 3
demonstrate that the sharp diminution and disappearance of urine
production is associated with a comparable increase in water loss
from the gastrointestinal tract.
EXAMPLE 4
Rats with non-functioning kidneys.
Sixteen male Sprague-Dawley rats had their kidney function
terminated abruptly by urethral ligation. The rats were then
divided into a control group of 4 animals and an experimental group
of 12 animals. To ensure that all animals took in a constant
quantity of either Sephadex (G50) or a placebo, the Sephadex was
suspended in mineral oil and given to the experimental or treatment
group. A comparable mixture of mineral oil placebo was given to the
control group of animals. The results of the study are shown in
FIG. 3. A striking difference in survival time was noted. All
control animals were dead in less than 40 hours whereas the
experimentally treated group survived for more than 100 hours.
(Mean survival time: experimental group 103.25.+-.10 hours;
survival time for control group 36.25.+-.1.25 hours). During the
study period, the water intake in these animals did not differ
significantly. The control group took in an average of 0.73.+-.0.11
ml of water per hour and the group treated with Sephadex (G50) took
an average of 0.58.+-.0.04 ml of water per hour. Six of the treated
animals survived 5 days and one animal survived for 7 days. The
treated group received 1.4 grams of Sephadex per day per animal for
the duration of their survival. The congrol group received only
placeboes of mineral oil. All animals were permitted food and water
ad lib for the duration of their survival. Another group of 8
animals operated upon at a different time were submitted to
uretheral ligation to serve as controls. All of these animals died
between the first and second day.
Thus the addition of Sephadex to the regimen of these rats without
any kidney function resulted in an increase in mean survival time
of more than three-fold demonstrating that Sephadex exerts an
important beneficial effect upon the length of survival in uremia.
The information contained in the 3 preceding examples and the
present one demonstrates that Sephadex when given orally leads to
profound reduction in the rate of urine formation and produces a
comparable increase in the quantity of water excreted in the feces.
Further, when given to rats rendered uremic by uretheral ligation
(thereby preventing any urine excretion) it increases the survival
time three-fold. On the basis of this information, it would be
expected to behave in the same manner when used in humans without
renal function.
EXAMPLE 5
Six Sprague-Dawley rats were maintained under control conditions in
metabolic cages for a 5 day period during which time food intake
was weighed carefully while they were permitted food ad lib. They
were also permitted free access to water. During this control
period, the daily food intake averaged 20.69.+-.0.82 (SEM) grams
per day. Beginning on day 6, five of the animals were given food
mixed with 50% Sephadex (G 50) and a sixth animal served as a
control to document weight changes in an animal not receiving
Sephadex during this period. Balance studies were continued
throughout this period and daily food intake measured. The results
of this study are shown in FIG. 4. The grams of food ingested by
the group of animals receiving Sephadex fell to 11.4.+-.0.95 grams
per day, a 50% reduction in food intake. During this period of
time, the average body weight of the group receiving Sephadex
dropped from 330 grams to 290 grams, an average weight loss per
animal of 40 grams or more than 10% of the body weight. The lone
control animal gained 25 grams during the same period and during
that period he continued to ingest an average daily weight of food
of 27.1.+-.1.98 grams.
In a second but somewhat shorter experiment a group of 27 animals
were divided into a group of 10 control animals and 17 animals
receiving Sephadex (G 50). The animals were kept in metabolic
cages; the control animals were given Purina rat chow and water ad
lib and the Sephadex animals received their food as a 50% mixture
of Sephadex (G 50) in pulverized Purina rat chow. During this study
the 17 animals receiving Sephadex lost an average of 5 grams of
body weight whereas the control group gained an average of 12
grams. The results of this study are shown in FIG. 5. These studies
provide evidence that the daily ingestion of Sephadex is associated
with the corresponding reduction in caloric or food intake.
EXAMPLE 6
FIG. 6A illustrates an experiment demonstrating the effect of
treatment with three different insoluble, hydrophilic, cross-linked
dextrans according to the present invention. A group of two rats
were given a diet which consisted of 50% by weight Sephadex G-50
and 50% normal rat chow. Another group of 2 rats were given a diet
which consisted of 50% by weight Sephadex G-100 and 50% normal rat
chow. A third group consisting of a single rat was given a diet
which consisted of 50% by weight of Sephadex G-200 and 50% normal
rat chow. A control group consisting of a single rat was given a
normal diet consisting entirely of normal rat chow. From FIG. 6A,
it can be seen that in each case treatment with an insoluble,
hydrophilic, cross-linked dextran according to the present
invention resulted in a substantially reduced volume of urine,
compared to the volume of the control group. At the same time, it
can be seen from FIG. 6B that the water content of the feces of
rats given a diet containing an insoluble hydrophilic, cross-linked
dextran according to the present invention is significantly higher
than the water content of the feces of the control group. Both
groups were permitted to consume as much water as they desired, and
their actual water consumption is shown in the table below:
______________________________________ DAILY VOLUME OF WATER
CONSUMED (IN MILLILITERS) Day Control 50% G-50 50% G-100 50% G-200
______________________________________ 1 52 32 18 41 2 46 30 43 33
3 42 24 40 0 4 30 35 55 52 5 40 58 48 50 6 50 65 69 60 7 50 60 75
50 ______________________________________
EXAMPLE 7
FIGS. 7A and 7B illustrate the results of an experiment
demonstrating the effects of varying the amount of preferred
insoluble, hydrophilic, cross-linked dextrans in the diets of rats.
A group of 2 rats were given a diet which consisted of 10% by
weight Sephadex G-100 and 90% by weight normal rat chow. Another
group of 2 rats were given a diet which consisted of 25% by weight
Sephadex G-100 and 75% by weight normal rat chow. A third group of
2 rats were given a diet consisting of 50% by weight Sephadex G-100
and 50% by weight normal rat chow. Each group was given this diet
for a period of 5 consecutive days, and then each group was
transferred to a normal diet consisting entirely of rat chow. After
a period of four days of a normal diet, each group was again
tested. FIG. 7A illustrates the results of the varying diets on the
daily volume of urine of each group. It will be noted that in every
case, the volume of urine of rats consuming a diet including an
insoluble, hydrophilic, cross-linked dextran according to the
present invention is substantially less than the volume of urine of
the same group on a normal diet. It will further be observed that
in every case, as the concentration of an insoluble, hydrophilic,
cross-linked dextran is increased, the volume of urine in the
treated group decreases. That is, the average daily volume of urine
of rats given a diet including 25% by weight Sephadex G-100 is
significantly less than the daily volume of urine of rats given a
diet containing only 10% by weight Sephadex G-100. Similarly, the
daily volume of urine of rats given a diet consisting of 50% by
weight Sephadex G-100 is significantly less than the daily volume
of urine of rats given a diet containing only 25% by weight
Sephadex G-100. Thus, it may be seen that although amounts as
little as 10% by weight of an insoluble, hydrophilic, cross-linked
dextran according to the present invention is effective in
substantially reducing the daily volume of urine, concentrations as
high as 50% by weight of the total diet are preferred. FIG. 7B
illustrates the water content of the feces of each of these groups
of rats, again compared to the water content of the feces of the
same rats fed a normal diet. In every case, it will be noted that
the effect of treatment with an insoluble, hydrophilic,
cross-linked dextran according to the present invention was to
increase the water content of the feces of rats so treated,
compared to rats consuming a normal diet. In every case, each rat
was permitted to consume as much water as desired. The actual water
consumed by each group of rats is listed in the table below:
______________________________________ DAILY VOLUME OF WATER
CONSUMED (IN MILLILITERS) Day 10% G-100 25% G-100 50% G-100
______________________________________ Sephadex-Containing Diet 1
68 103 73 2 56 81 73 3 69 69 73 4 61 74 78 5 55 78 67 Normal Diet 1
45 52 45 2 53 46 55 3 45 42 54
______________________________________
These experiments show that diets containing insoluble,
hydrophilic, cross-linked carbohydrates according to the present
invention are able to divert water elimination from the renal route
to the gastrointestinal route, and remove water from the body by
the gastrointestinal route. These pharmalogical properties are of
significant therapeutic value in the treatment of edema, water
intoxication in chronic renal failure, and in the treatment of
other forms of fluid retention such as congestive heart failure,
cirrhosis of the liver and other disorders associated with
refractory swelling. These pharmalogical properties are also useful
as a means of reducing caloric intake, in the treatment of
conditions such as obesity. Although the above experiments were
conducted with animals other than human beings, preliminary
experiments indicate that the insoluble, hydrophilic, cross-linked
carbohydrates according to the present invention exhibit the same
pharmalogical properties when used to treat human beings as in the
treatment of other animals.
The present invention has been elucidated by the examples described
above, but the invention is not limited thereto. It is understood
that various other modifications will be apparent to and can
readily be made by those skilled in the art without departing from
the scope and spirit of this invention. Accordingly, it is not
intended that the scope of the claims appended hereto be limited to
the description set forth herein, but rather that the claims be
construed as encompassing all the features of the present invention
including all features which would be treated as equivalents
thereof by those skilled in the art to which this invention
pertains.
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